Thiophene and bioisostere derivatives as new MMP12 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.10.087

A new MMP12 inhibitor series has been identified containing a thiophene moiety. Different approaches have been considered to replace this potential toxicophore. α-Fluorothiophene derivatives were the most interesting compounds. Their synthesis is presente

Full text of DOI:10.1016/j.bmcl.2010.10.087

Bioorganic & Medicinal Chemistry Letters 21 (2011) 528–530
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Thiophene and bioisostere derivatives as new MMP12 inhibitors
Matthew Badland b, , Delphine Compère a, , Karine Courté a, Anne-Claude Dublanchet a, Stéphane Blais a,
⇑
⇑
Ajith Manage b, Guillaume Peron b, Roger Wrigglesworth a
a Pfizer Global Research and Development, Fresnes Laboratories, 3–9 Rue de la Loge, F-94265 Fresnes Cedex, France
b Evotec OAI, 151 Milton Park, Abingdon, Oxon OX14 SD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A new MMP12 inhibitor series has been identified containing a thiophene moiety. Different approaches
Received 28 September 2010
Revised 15 October 2010
Accepted 16 October 2010
Available online 9 November 2010
have been considered to replace this potential toxicophore.
interesting compounds. Their synthesis is presented.
a
-Fluorothiophene derivatives were the most
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
MMP12 inhibitor series
Thiophene moiety
a-Fluorothiophene derivatives
Isothiazole
Since MMP12 has been shown to play an important role in
et al.3a However, modifications to this substructure could mitigate
or avoid toxicity by introduction of bioisosteres, 2,5-substitution
on the thiophene, or ring deactivation by addition of adjacent
functionality.5
Inthiscontext, wereporthereinthesynthesisandbiologicaleval-
uation of isothiazole core structures A and B and fluorothiophene
derivatives C where the thiophene reactive position has been
blocked with a fluorine atom (Fig. 2).
Thepreparationofmethyl4-(4-bromophenyl)-5-fluorothiophene
carboxylate E is described. This versatile template, as well as the
isothiazole core analog D, lead to the synthesis of elaborated targeted
compounds potentially inhibiting MMP12.
The concept of bioisosterism has been widely utilized as one
strategy for lead optimization in the discovery of new drugs.6
The bioisostere approach has been shown to be useful to augment
potency or to modify certain physiological properties of a lead
compound. The isosteric replacement of the thiophene moiety
was motivated here to avoid a potential toxicophore and to in-
crease future confidence in this promising series. Isothiazole core
structure A has been identified as a bioisostere of the thiophene
tissue destruction as well as in macrophage recruitment in the
lungs following cigarette smoking, this enzyme has become an
attractive target for COPD (Chronic Obstructive Pulmonary
Disease).1
The original hit 1 characterized by a 4-phenylthiophene-2-
carboxamide structure was identified in HTS with a moderate
potency (13 lM). The key strategy consists in identifying MMP12
inhibitors which bind to the S10 pocket and do not interact with
the enzyme on its catalytic domain unlike zinc chelators. This
should ensure a good selectivity profile against other MMPs struc-
turally close to MMP12 (MMP13, 2, 3) and minimize the classical
side effects observed with other MMPs inhibitors.
A full analoging program has been developed around this hit.2
In particular in this paper, synthetic efforts have been focused on
replacement of the central thiophene core or on substitution of
the reactive position
a to the sulfur atom.
Non fused thiophene is considered a potential toxicophore3
leading to toxicity particularly hepatotoxicity, immunotoxicity
and nephrotoxicity.4 Removal of some of the thiophene containing
therapeutic agents from use due to hepatoxicities has led to an in-
creased effort in understanding the cause of these toxic events. The
metabolism of thiophenes is principally mediated by cytochrome
P450. Thiophenes undergo hydroxylation at the carbon atoms adja-
cent to the sulfur atom and are converted to 2 or 5-hydroxythioph-
enes as described in the well documented article related to five-
membered aromatic ring biotransformation reactions by Dalvie
MeO
H
N
N
O
S
O
⇑
Corresponding authors.
E-mail address: matthew.badland@pfizer.com (M. Badland).
Figure 1. Compound 1, initial hit identified from a mass screen of MMP12 catalytic
domain.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.10.087

M. Badland et al. / Bioorg. Med. Chem. Lett. 21 (2011) 528–530
529
R1
N
R1
S
R1
a
H
N
H
N
H
N
O2N
Br
CN
F
CN
S
S
S
Route 1
R2
R2
R2
F
S
N
S
O
O
O
b
A
B
C
Br
Figure 2. Isothiazole core structures A and B and
a
-fluorothiophene C.
c
5
(H, OMe)
(H, OMe)
F
S
Route 2
O
O
Br
Br
C'
Scheme 2. Reagents and conditions: Route 1 (a) KF, PPh4Br, phtaloyldichloride,
sulfolane; (b) Br2, 10 h at ꢀ5 °C; Route 2 (c) with aldehyde as starting material:
Selectfluor™ in CH3CN/H2O, five days at 70 °C, 90% conversion HPLC; with methyl
ester as starting material: Selectfluor™ in CH3CN, five days until 70 °C, 30%
conversion HPLC and degradation.
O
O
O
N
F
S
S
O
D
E
and issues of reproducibility on larger scale. The alternative route
we considered was made use of the reagent Selectfluor™ (so called
F-TEDA-BF4), a convenient source of F+, which is commercially
available and with the advantage to be relatively stable and easy
to handle.12 To our knowledge, electrophilic fluorinating agents
(Selectfluor™ and analogous derivatives) have been previously
Figure 3. General templates leading to potential MMP12 inhibitors.
Br
H2N
Br
a, b
c, d
O
.HCl
S
S
S
N
used on
a
position of thiophene ring but with low yields.13 In
N
N
O
our conditions, the reaction was incomplete even if the conversion
was satisfactory in the case of 4-bromothiophene carbaldehyde
(90% conversion monitored by HPLC). Unfortunately it was impos-
sible to isolate fluorothiophene derivative C0 from starting material
using classical separation conditions.
F3CO
e, f
F3CO
O
OH
g, h
H
As a second approach, we decided to start from a scaffold al-
ready bearing R1 as a substituent (Scheme 3).14 Balz-Schiemann
reaction failed in our conditions (Route 1, step b). Indeed literature
references can be found where these conditions were successful on
thiophene moiety in position 3 or 415 but not in the position adja-
cent to sulfur atom.16 It is presumably related to a stability issue of
OH
N
S
S
N
N
O
O
Scheme 1. Reagents and conditions: (a) NaOH, TBME; (b) HNO3, NaNO2 in H3PO4
then CuBr–HBr; (c) CrO3, H2SO4; (d) H2SO4, MeOH; (e) 4-trifluoromethoxy-
phenylboronic acid, Pd(PPh3)4, K3PO4 aq 2 M, DME, 80 °C; (f) LiOH, MeOH/H2O;
(g) trans 4-amino methyl-cycloxanecarboxylic acid ethyl ester, HATU, DIPEA, DMF;
(h) LiOH, EtOH/H2O.
a
-aminothiophene17 even though we did not observe it with our
substrate. We were successful in identifying Selectfluor™ as a good
alternative in this case (Route 2) where the separation of the non-
fluoronated starting material is carried out as the last step using re-
verse phase chromatography (10% yield for steps c and d).
Table 1 shows the activity of the different bioisosteric replace-
ments of thiophene ring. Fluorothiophene 5 appears to show prom-
ising activity when compared to the parent compound 1.
Encouraged by this result, we were interested in providing a gen-
ring and has been prepared according to the literature procedure.7
The general template D described in Figure 3 has been made via a
similar route to that of the original lead, Figure 1, with the inclu-
sion of the bromo-phenyl ring for subsequent Suzuki coupling
and the introduction of diversity. Conversely, isomer isothiazoles
B are less common as five-membered heteroaromatic bioisosteric
rings in drugs and no preparation has been reported in the last
few decades.
The chemistry of the isothiazole derivative B, from which first
close analogous were prepared in 1959,8 has been performed from
commercially available 5-amino-3-methylisothiazole (Scheme 1).
As anticipated in the original paper with 3-methylisothiazole, the
bottleneck was the oxidation of the methyl group due to its rela-
tively inert character (13% yield for step c). We nevertheless ob-
tained several grams of the scaffold intermediate B0 leading to
the expected compound 4.
In the field of bioisosteric chemistry, our effort was directed to
the development of fluorothiophenes where the reactive position
adjacent to sulfur atom is blocked with a fluorine atom. Very few
viable synthetic routes exist for the synthesis of the 4-bromo-5flu-
orothiophene-2-carbonyl template C0 especially if we exclude use
of hazardous gases like perchloryl fluoride (FClO3).9 Our first ap-
proach consisted in the construction of this elaborate thiophene
moiety with a fluorine atom as reactive position blocker and bro-
mine in position 4 for the following Suzuki coupling steps. In our
initial trials, we had expected to obtain derivative C0 via a fluoro-
denitration reaction10 followed by a regioselective bromination
(Scheme 2, Route 1).11 Such a route was difficult to perform due
to the loss of volatile compound 5-fluorothiophene-2-carbonitrile
eral method to access the a-fluorothiophene ring.
The approach using Selectfluor™ has been extended to com-
pounds such as E0 leading to E (Scheme 4), which is a key template
in our program. One equivalent of the reagent provided 60%
conversion the desired compound but contaminated by starting
material. Purification on silica gel in isocratic conditions
R1
R1
R1
a
b
O
O
O
O2N
H2N
F
S
S
S
O
O
O
Route 1
R1
R1
R1
R2
=
=
OCF3
CO2H
c, d, e, f
Route 2
H
O
N
R2
F
S
S
O
O
5
Scheme 3. Reagents and conditions: Route 1 (a) H2, Pd/C 10% in MeOH; (b) NaNO2,
HBF4 0 °C then heating: obtention of reduced compound; Route 2 (c) Selectfluor™,
3 h at 50 °C in CH3CN, 50% conversion HPLC; (d) LiOH in EtOH/H2O; (e) trans 4-
(aminomethyl)cycloxanecarboxylic acid ethyl ester or 4-(trifluoromethoxy)aniline,
HATU, DIPEA, DMF; (f) LiOH, EtOH/H2O.

530
M. Badland et al. / Bioorg. Med. Chem. Lett. 21 (2011) 528–530
Table 1
ranges (Table 2). Their synthesis is based on versatile palladium-
catalyzed coupling chemistry followed by a peptidic coupling se-
quence as previously demonstrated2 and shown in Scheme 3
(Route 2).
In vitro profile of bioisosteric replacement of thiophene moiety
F3CO
O
OH
In summary, we have developed a strategy to access
a-fluoro-
thiophene derivatives as new MMP12 inhibitors. Even though in
our studies no evidence of toxicity related to the thiophene struc-
ture has been detected (Ames Biolum and Reactive Metabolites
negative) so far, based on previous reports3 we consider the pres-
ent series potentially less toxicophoric. Besides having blocked the
reactive position of the thiophene moiety, we have also moderately
increased the activity when comparing compound 5 to the non
fluoro derivative 1 (Fig. 1).
H
N
S
O
a
Compd
Core structure variation
IC50 (lM) MMP12
2
0.40
3.6
S
3
4
5
Acknowledgements
N
S
The authors would like to thank Dr. Claude Wakselman and Dr.
Emmanuel Magnier for helpful advice in fluorine chemistry.
31
S
N
References and notes
0.14
F
S
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Br
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a
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O
O
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F
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E0
E
Scheme 4. (a) Selectfluor overnight at 70 °C, 60% conversion HPLC.
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a
-fluorothiophene
R1
H
N
R2
F
S
O
R1
R2
IC50 (lM) MMP12
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OCF3
OCF3
CO2H
0.20
Ph
CONH2
0.085
0.007
0.024
Ph
O
O
CO2H
CO2H
CO2H
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´
´
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(heptane/dichloromethane: 1/1) provided the pure derivative E
with a 40% yield. More than ten grams of intermediate E has been
produced by this method.
This synthetic strategy has been successfully applied to the
preparation of various MMP12 inhibitors with nanomalor activity